The causes of diabetes mellitus are not yet known, although both genetics and environment seem to be major factors. Type 1 diabetes, also known as insulin-dependent diabetes mellitus (IDDM), is an autoimmune disease in which the responsible autoantigen is still unidentified. Since their insulin-producing pancreatic cells are destroyed, Type 1 diabetics need to take insulin parenterally to survive. On the other hand, type 2 diabetes, also called non-insulin-dependent diabetes mellitus (NIDDM), the more common form, is a metabolic disorder resulting from the body's inability to make a sufficient amount of insulin or to properly use the insulin that is produced. Impaired insulin secretion and insulin resistance are considered the major defects; however, the precise genetic factors involved in the mechanism remain unknown.
Other than insulin administered parenterally and as shown in Table 1, there are generally four major classes of oral hypoglycemic agents currently used in the treatment of diabetes mellitus:
TABLE 1ApprovedMechanisms ofClassDrugsActionLimitationsSulfonylureafour (1ststimulates pancreashypoglycemia;generation)to release moremay increaseandinsulincardiovasculartwo (2ndrisk; contra-generation)indicated in liverand renaldysfunction;hyperinsulinemiaBiguanidemetforminreduces glucoselactic acidosis; GIproduction byside effectsliver; improvesinsulin sensitivityAlpha-acarbosereduces glucoseGI side effects;glucosidaseabsorption by gutrequires frequentinhibitorpostprandialdosingThiazolidinedionetroglitazonestimulates nuclearedema; contra-(withdrawn)PPAR-gammaindicated in heartrosiglitazonereceptor; reducesfailure; long onsetpioglitazoneinsulin resistanceof action; weightgain; frequentliver functiontesting
As is shown in the above table, each of the current agents available for use in treatment of diabetes mellitus has several disadvantages. Accordingly, there is a need for the identification and development of new agents, particularly, water soluble agents which can be orally administered, for use in the treatment of diabetes mellitus and other hyperglycemic disorders.
Moreover, while the thiazolidinedione class has gained more widespread use in recent years as insulin sensitizers to combat “insulin resistance”, a condition in which the patient becomes less responsive to the effects of insulin, there is a need for frequent liver testing for patients using these compounds. In fact, the known thiazolidinediones are not effective for a significant portion of the patient population. In addition, the first drug in this class to be approved by the FDA, troglitazone, was withdrawn from the market due to problems of liver toxicity. Thus, there is a continuing need for nontoxic, more widely effective insulin sensitizers.
As indicated above, the invention is also directed to the treatment of immunological diseases or inflammation, in particular, such diseases as are mediated by cytokines, COX-2 and iNOS. The principal elements of the immune system are macrophages or antigen-presenting cells, T cells and B cells. Macrophages are important mediators of inflammation and also provide the necessary “help” for T cell stimulation and proliferation. For example, macrophages make the cytokines IL-1, IL-12 and TNF-alpha, all of which are potent pro-inflammatory molecules. Cytokine production may lead to the secretion of other cytokines, altered cellular function, cell division or differentiation. In addition, activation of macrophages results in the induction of enzymes, such as COX-2 and iNOS, and in the production of free radicals capable of damaging normal cells. Many factors activate macrophages, including bacterial products, superantigens and interferon gamma. It is believed that phosphotyrosine kinases and other cellular kinases are involved in the activation process. Since macrophages are sentinel to the development of an immune response, agents that modify their function, specifically their cytokine secretion profile, are likely to determine the direction and potency of the immune response.
Inflammation is the body's normal response to injury or infection. However, in inflammatory diseases such as rheumatoid arthritis, pathologic inflammatory processes can lead to morbidity and mortality. The cytokine tumor necrosis factor-alpha (TNF-alpha) plays a central role in the inflammatory response and has been targeted as a point of intervention in inflammatory disease. TNF-alpha is a polypeptide hormone released by activated macrophages and other cells. At low concentrations, TNF-alpha participates in the protective inflammatory response by activating leukocytes and promoting their migration to extravascular sites of inflammation (Moser et al., J Clin Invest, 83:444-55, 1989). At higher concentrations, TNF-alpha can act as a potent pyrogen and induce the production of other pro-inflammatory cytokines (Haworth et al., Eur J Immunol, 21:2575-79, 1991; Brennan et al., Lancet, 2:244-7, 1989). TNF-alpha also stimulates the synthesis of acute-phase proteins. In rheumatoid arthritis, a chronic and progressive inflammatory disease affecting about 1% of the adult U.S. population, TNF-alpha mediates the cytokine cascade that leads to joint damage and destruction (Arend et al., Arthritis Rheum, 38:151-60, 1995). Inhibitors of TNF-alpha, including soluble TNF receptors (etanercept) (Goldenberg, Clin Ther, 21:75-87, 1999) and anti-TNF-alpha antibody (infliximab) (Luong et al., Ann Pharmacother, 34:743-60, 2000), the contents of each of which are incorporated herein by reference, have recently been approved by the U.S. Food and Drug Administration (FDA) as agents for the treatment of rheumatoid arthritis.
Elevated levels of TNF-alpha have also been implicated in many other disorders and disease conditions, including cachexia (Fong et al., Am J Physiol, 256:R659-65, 1989), septic shock syndrome (Tracey et al., Proc Soc Exp Biol Med, 200:233-9, 1992), osteoarthritis (Venn et al., Arthritis Rheum, 36:819-26, 1993), inflammatory bowel disease such as Crohn's disease and ulcerative colitis (Murch et al., Gut, 32:913-7, 1991), Behcet's disease (Akoglu et al., J Rheumatol, 17:1107-8, 1990), Kawasaki disease (Matsubara et al., Clin Immunol Immunopathol, 56:29-36, 1990), cerebral malaria (Grau et al., N Engl J Med, 320:1586-91, 1989), adult respiratory distress syndrome (Millar et al., Lancet 2:712-4, 1989), asbestosis and silicosis (Bissonnette et al., Inflammation, 13:329-39, 1989), pulmonary sarcoidosis (Baughman et al., J Lab Clin Med, 115:36-42, 1990), asthma (Shah et al., Clin Exp Allergy, 25:1038-44, 1995), AIDS (Dezube et al., J Acquir Immune Defic Syndr, 5:1099-104, 1992), meningitis (Waage et al., Lancet, 1:355-7, 1987), psoriasis (Oh et al., J Am Acad Dermatol, 42:829-30, 2000), spondyloarthritides such as ankylosing spondylitis (Braun et al., Curr Opin Rheumatol 13:245-9, 2001; Marzo-Ortega et al., Arthritis Rheum 44:2112-7, 2001), graft versus host reaction (Nestel et al., J Exp Med, 175:405-13, 1992), multiple sclerosis (Sharief et al., N Engl J Med, 325:467-72, 1991), systemic lupus erythematosus (Maury et al., Int J Tissue React, 11:189-93, 1989), diabetes (Hotamisligil et al., Science, 259:87-91, 1993) and atherosclerosis (Bruunsgaard et al., Clin Exp Immunol, 121:255-60, 2000), the contents of each of which are incorporated herein by reference. It can be seen from the references cited above that inhibitors of TNF-alpha are potentially useful in the treatment of a wide variety of diseases.
Interleukin-6 (IL-6) is another pro-inflammatory cytokine that exhibits pleiotropy and redundancy of action. IL-6 participates in the immune response, inflammation and hematopoiesis. It is a potent inducer of the hepatic acute phase response and is a powerful stimulator of the hypothalamic-pituitary-adrenal axis that is under negative control by glucocorticoids. IL-6 promotes the secretion of growth hormone but inhibits release of thyroid stimulating hormone. Elevated levels of IL-6 are seen in several inflammatory diseases, and inhibition of the IL-6 cytokine subfamily has been suggested as a strategy to improve therapy for rheumatoid arthritis (Carroll et al., Inflamm Res, 47:1-7, 1998). In addition, IL-6 has been implicated in the progression of atherosclerosis and the pathogenesis of coronary heart disease (Yudkin et al., Atherosclerosis, 148:209-14, 1999). Overproduction of IL-6 is also seen in steroid withdrawal syndrome, conditions related to deregulated vasopressin secretion, and osteoporosis associated with increased bone resorption, such as in cases of hyperparathyroidism and sex-steroid deficiency (Papanicolaou et al., Ann Intern Med, 128:127-37, 1998). Since excessive production of IL-6 is implicated in several disease states, it is highly desirable to develop compounds that inhibit IL-6 secretion.
The cytokine IL-1 beta also participates in the inflammatory response. It stimulates thymocyte proliferation, fibroblast growth factor activity, and the release of prostaglandin from synovial cells. Elevated or unregulated levels of the cytokine IL-1 beta have been associated with a number of inflammatory diseases and other disease states, including but not limited to adult respiratory distress syndrome (Meduri et al, Chest 107:1062-73, 1995), allergy (Hastie et al, Cytokine 8:730-8, 1996), Alzheimer's disease (O'Barr et al, J Neuroimmunol 109:87-94, 2000), anorexia (Laye et al, Am J Physiol Regul Integr Comp Physiol 279:R93-8, 2000), asthma (Sousa et al, Thorax 52:407-10, 1997), atherosclerosis (Dewberry et al, Arterioscler Thromb Vasc Biol 20:2394-400, 2000), brain tumors (Ilyin et al, Mol Chem Neuropathol 33:125-37, 1998), cachexia (Nakatani et al, Res Commun Mol Pathol Pharmacol 102:241-9, 1998), carcinoma (Ikemoto et al, Anticancer Res 20:317-21, 2000), chronic arthritis (van den Berg et al, Clin Exp Rheumatol 17:S105-14, 1999), chronic fatigue syndrome (Cannon et al, J Clin Immunol 17:253-61, 1997), CNS trauma (Herx et al, J Immunol 165:2232-9, 2000), epilepsy (De Simoni et al, Eur J Neurosci 12:2623-33, 2000), fibrotic lung diseases (Pan et al, Pathol Int 46:91-9, 1996), fulminant hepatic failure (Sekiyama et al, Clin Exp Immunol 98:71-7, 1994), gingivitis (Biesbrock et al, Monogr Oral Sci 17:20-31, 2000), glomerulonephritis (Kluth et al, J Nephrol 12:66-75, 1999), Guillain-Barre syndrome (Zhu et al, Clin Immunol Immunopathol 84:85-94, 1997), heat hyperalgesia (Opree et al, J Neurosci 20:6289-93, 2000), hemorrhage and endotoxemia (Parsey et al, J Immunol 160:1007-13, 1998), inflammatory bowel disease (Olson et al, J Pediatr Gastroenterol Nutr 16:241-6, 1993), leukemia (Estrov et al, Leuk Lymphoma 24:379-91, 1997), leukemic arthritis (Rudwaleit et al, Arthritis Rheum 41:1695-700, 1998), systemic lupus erythematosus (Mao et al, Autoimmunity 24:71-9, 1996), multiple sclerosis (Martin et al, J Neuroimmunol 61:241-5, 1995), osteoarthritis (Hernvann et al, Osteoarthritis Cartilage 4:139-42, 1996), osteoporosis (Zheng et al, Maturitas 26:63-71, 1997), Parkinson's disease (Bessler et al, Biomed Pharmacother 53:141-5, 1999), POEMS syndrome (Gherardi et al, Blood 83:2587-93, 1994), pre-term labor (Dudley, J Reprod Immunol 36:93-109, 1997), psoriasis (Bonifati et al, J Biol Regul Homeost Agents 11:133-6, 1997), reperfusion injury (Clark et al, J Surg Res 58:675-81, 1995), rheumatoid arthritis (Seitz et al, J Rheumatol 23:1512-6, 1996), septic shock (van Deuren et al, Blood 90:1101-8, 1997), systemic vasculitis (Brooks et al, Clin Exp Immunol 106:273-9, 1996), temporal mandibular joint disease (Nordahl et al, Eur J Oral Sci 106:559-63, 1998), tuberculosis (Tsao et al, Tuber Lung Dis 79:279-85, 1999), viral rhinitis (Roseler et al, Eur Arch Otorhinolaryngol Suppl 1:S61-3, 1995), the contents of each of which are incorporated herein by reference, and pain and/or inflammation resulting from strain, sprain, trauma, surgery, infection or other disease processes. Since overproduction of IL-1 beta is associated with numerous disease conditions, it is desirable to develop compounds that inhibit the production or activity of IL-1 beta.
Cyclooxygenase is an enzyme that catalyzes a rate-determining step in the biosynthesis of prostaglandins, which are important mediators of inflammation and pain. The enzyme occurs as at least two distinct isomers, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The COX-1 isomer is constitutively expressed in the gastric mucosa, platelets and other cells and is involved in the maintenance of homeostasis in mammals, including protecting the integrity of the digestive tract. The COX-2 isomer, on the other hand, is not constitutively expressed but rather is induced by various agents, such as cytokines, mitogens, hormones and growth factors. In particular, COX-2 is induced during the inflammatory response (DeWitt DL, Biochim Biophys Acta, 1083:121-34, 1991; Seibert et al., Receptor, 4:17-23, 1994.). Aspirin and other conventional non-steroid anti-inflammatory drugs (NSAIDs) are non-selective inhibitors of both COX-1 and COX-2. They can be effective in reducing inflammatory pain and swelling, but since they hamper the protective action of COX-1, they produce undesirable side effects of gastrointestinal pathology. Therefore, agents that selectively inhibit COX-2 but not COX-1 are preferable for treatment of inflammatory diseases. Recently, a diarylpyrazole sulfonamide (celecoxib) that selectively inhibits COX-2 has been approved by the FDA for use in the treatment of osteoarthritis and adult rheumatoid arthritis (Luong et al., Ann Pharmacother, 34:743-60, 2000; Penning et al., J Med Chem, 40:1347-65, 1997). Another selective COX-2 inhibitor, rofecoxib, has been approved by the FDA for treatment of osteoarthritis, acute pain and primary dysmenorrhea (Scott and Lamb, Drugs, 58:499-505, 1999; Morrison et al., Obstet Gynecol, 94:504-8, 1999; Saag et al, Arch Fam Med, 9:1124-34, 2000). COX-2 is also expressed in many cancers and precancerous lesions, and there is mounting evidence that selective COX-2 inhibitors may be useful for treating and preventing colorectal, breast and other cancers (Taketo M M, J Natl Cancer Inst, 90:1609-20, 1998; Fournier et al., J Cell Biochem Suppl, 34:97-102, 2000; Masferrer et al., Cancer Res, 60:1306-11, 2000), the contents of each of which are incorporated herein by reference. In 1999 celecoxib was approved by the FDA as an adjunct to usual care for patients with familial adenomatous polyposis, a condition which, left untreated, generally leads to colorectal cancer.
Production of nitric oxide by iNOS has been associated with both beneficial and detrimental effects in inflammation, inflammatory diseases and related disorders. For example, deleterious effects have been implicated in the pathogenesis of abdominal aortic aneurysms (Johanning et al, J Vasc Surg 33:579-86, 2001), acute endotoxemia (Henningsson et al, Am J Physiol Cell Physiol 280:C1242-54, 2001), amyotrophic lateral sclerosis (Sasaki et al, Neurosci Lett 291:44-8, 2000), atherosclerosis (Behr-Roussel et al, Circulation 102:1033-8, 2000), bladder cancer (Wolf et al, Virchows Arch 437:662-6, 2000), colon cancer (Watanabe et al, Biofactors 12:129-33, 2000), cystitis (Alfieri et al, Naunyn Schmiedebergs Arch Pharmacol 363:353-7, 2001), HIV-1 encephalitis (Zhao et al, J Neuroimmunol 115:182-91, 2001), inflammatory bowel disease (Singer et al, Gastroenterology 111:871-85, 1996), multiple sclerosis (Pozza et al, Brain Res 855:39-46, 2000), osteoarthritis (Pelletier et al, Osteoarthritis Cartilage 7:416-8, 1999), osteoporosis (Armour et al, J Bone Miner Res 14:2137-42, 1999), portal hypertension (Schroeder et al, Dig Dis Sci Dec 45:2405-10, 2000), pulmonary edema in endotoxin shock (Lee et al, Clin Exp Pharmacol Physiol 28:315-20, 2001), rheumatoid arthritis (van't Hof et al, Rheumatology (Oxford) 39:1004-8, 2000), sepsis (Nishina et al, Anesth Analg 92:959-66, 2001), severe burn/smoke inhalation injury (Soejima et al, Am J Respir Crit Care Med 163:745-52, 2001), and ulcerative colitis (Ikeda et al, Am J Gastroenterol 92:1339-41, 1997), the contents of each of which are incorporated herein by reference. Since the production of nitric oxide by iNOS has been implicated in the pathogenesis of inflammatory and related immunological diseases, it is desirable to develop compounds that inhibit iNOS activity or expression.
Phosphodiesterases (PDEs) are responsible for the hydrolysis of intracellular cyclic adenosine and guanosine monophosphate (cAMP and cGMP), which converts these second messengers into their inactive forms. There are 11 major families of PDEs, designated PDE1 to PDE11. Type 4 phosphodiesterase (PDE4) is found in airway smooth muscle cells and in immune and inflammatory cells. PDE4 activity has been associated with a wide variety of inflammatory and autoimmune diseases, and PDE4 inhibitors have been studied as potential therapeutic agents for such diseases as asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, multiple sclerosis and type 2 diabetes (Burnouf and Pruniaux, Current Pharm Des, 8:1255-96, 2002; Dal Piaz and Giovannoni, Eur J Med Chem, 35:463-80, 2000). Type 3 phosphodiesterase (PDE3) is localized in platelets and cardiac and vascular smooth muscle cells. Inhibitors of PDE3 have been proposed as possible drugs for the treatment of acute respiratory distress syndrome (Schermuly et al, J Pharmacol Exp Ther, 292:512-20, 2000), cancer (Shimizu et al, Anticancer Drugs, 13:875-80, 2002; Murata et al, Anticancer Drugs, 12:79-83, 2001), cardiomyopathy (Alharethi and Movsesian, Expert Opin Investig Drugs, 11:1529-36, 2002), congestive heart failure (Movsesian, J Am Coll Cardiol, 34:318-24, 1999), erectile dysfunction (Kuthe et al, Curr Opin Investig Drugs, 3:1489-95, 2002), and T-cell-mediated autoimmune disorders (Bielekova et al, J Immunol 164:1117-24, 2000), the contents of each of which are incorporated herein by reference.
Activation of lymphocyte and macrophage immune response to pathogens involve complex intracellular signaling pathways involving a cascade of various phosphorylating enzymes, kinases that ultimately regulate cytokine production and cell apoptosis. Key kinases include p44/42 MAP kinase (also known as ERK1/ERK2), P38 MAP kinase, MEK, and IRAK/NFkB. While different processes utilize different aspects of the pathway, the bacterial coat-derived protein LPS has been shown to activate multiple mitogen-activated protein kinases, including the extracellular signal-regulated receptor kinases ERK1 and ERK2. LPS-induced TNF-alpha production by human monocytes involves activation of ERK1/ERK2 (van der Bruggen et al, Infect Immun, 67:3824-9, 1999). As TNF-alpha is a key mediator of autoimmune disease, blocking the ERK pathway has potential for the treatment of inflammatory and immunological diseases such as lupus (Yi et al, J Immunol, 165:6627-34, 2000), rheumatoid arthritis (Neff et al, Cell Microbiol, 3:703-12, 2001; Schett et al, Arthritis Rheum, 43:2501-12, 2000), psoriasis (van der Bruggen et al, Infect Immun, 67:3824-9, 1999) and destruction of pancreatic islet beta cells in Type I diabetes (Pavlovic et al, Eur Cytokine Netw 11:267-74, 2000), the contents of each of which are incorporated herein by reference.
It will be appreciated from the foregoing that, while there have been extensive prior efforts to provide compounds for inhibiting, for example, TNF-alpha, IL-1 beta, IL-6, COX-2, PDE4 or other agents considered responsible for inflammation or inflammatory diseases, e.g. arthritis, there still remains a need for new and improved compounds for effectively treating or inhibiting such diseases. A principal object of the invention is to provide compounds which are effective for such treatments as well as for the treatment of, for example, diabetes, coronary heart disease, insulin resistance and related disorders.